Perixome Proliferator Activated Receptors (PPARs) are orphan receptors belonging to the steroid/retinoid receptor superfamily of ligand-activated transcription factors. See, for example Willson T. M. and Whali, W., Curr. Opin. Chem. Biol., 1, pp 235-241 (1997) and Willson T. M. et. Al., J. Med. Chem., 43, P527-549 (2000). The binding of agonist ligands to the receptor results in changes in the expression level of mRNAs encoded by PPAR target genes.
Three mammalian Peroxisome Proliferator-Activated Receptors have been isolated and termed PPAR-alpha, PPAR-gamma, and PPAR-delta (also known as NUC1 or PPAR-beta). These PPARs regulate expression of target genes by binding to DNA sequence elements, termed PPAR response elements (PPRE). To date, PPRE's have been identified in the enhancers of a number of genes encoding proteins that regulate lipid metabolism suggesting that PPARs play a pivotal role in the adipogenic signalling cascade and lipid homeostasis (H. Keller and W. Wahli, Trends Endocrinol. Metab. 291-296, 4 (1993)).
It has been reported that the thiazolidinedione class of compounds including rosiglitazone and pioglitazone are potent and selective activators of PPAR-gamma and bind directly to the PPAR-gamma receptor (J. M. Lehmann et al., J. Biol. Chem. 12953-12956, 270 (1995)), providing evidence that PPAR-gamma is a possible target for the therapeutic actions of the thiazolidinediones. Since this observation, activation of this nuclear hormone receptor has been shown to have pleiotropic metabolic and nonhypoglycemic effects. Clinical use of the agents in the treatment of Type 2 diabetes mellitus (or non insulin dependent diabetes mellitus (NIDDM)) is associated with sensitization to the glucose lowering effects of insulin as well as potentiation of other biological actions of insulin in target tissues. When used as monotherapy, there are reports of fluid retention resulting in volume expansion and, in some patients, clinical edema. The incidence of edema appears to be increased when both these agents are used in combination with insulin (Nesto R. W. et al, 2003, Circulation, 108, 2941-2948). However, the mechanisms involved in these effects have not been well described but the nature of the presentation suggests an integrated physiological response which includes an effect on renal salt and water balance. PPAR gamma receptors have been found in the renal collecting duct (Guan Y. et al; 2001, Kidney Int. 60, 14-30) and, therefore, the PPAR gamma agonists might be involved directly in renal tubular metabolism or could have secondary effects on salt and water homeostasis.
Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most prevalent single gene disorders to affect humans with an incidence of approximately 1 in 1000 live births in all ethnic groups (Gabow P. A., 1993, N. Engl. J. Med. 329: 332-342). The disease is caused by mutations in the polycystin proteins that initiate a cascade of events resulting in the formation of multiple fluid-filled epithelial cysts which progressively destroys the architecture of the kidney leading to severe renal failure. Currently, no therapies exist for ADPKD which account for 8-10% of patients requiring kidney transplantation or dialysis (Gabow P. A., 1993, N. Engl. J. Med. 329: 332-342). It will therefore be appreciated that it is desirable to identify and develop treatments for this disease.
The development and growth of ADPKD cysts involve the proliferation of immature epithelial cells, changes in the extracellular matrix and the accumulation of fluid in the cyst cavity. This is driven by CAMP stimulated cell proliferation and CI-secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) CI-channel. Thus it is thought that inhibitors at the CF TR CI-channel may retard cyst growth principally by blocking fluid accumulation within the cyst lumen. (Hongyu Li et al., 2004, Kidney International 66; 1926-1938).
The present inventors have found that modulators of the peroxisome proliferator activated receptor gamma (PPAR gamma) may inhibit anion secretion via CFTR in renal cells and thus are of potential therapeutic benfefit in the treatment of renal diseases or conditions associated with abnormal ion flux, including ADPKD.